-
Article
Open AccessMarkers associated with genomic instability, immunogenicity and immune therapy responsiveness in Metaplastic carcinoma of the breast: Expression of γH2AX, pRPA2, P53, PD-L1 and tumor infiltrating lymphocytes in 76 cases
Metaplastic breast cancer (MpBC) is an aggressive subtype of breast carcinoma that is often resistant to conventional chemotherapy. Therefore, novel treatment strategies are urgently needed. Immune check point...
-
Article
Open AccessAddiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation
Inflammatory and oncogenic signaling converge in disease evolution of BCR–ABL-negative myeloproliferative neoplasms, clonal hematopoietic stem cell disorders characterized by gain-of-function mutation in JAK2 kin...
-
Article
Tumors overexpressing RNF168 show altered DNA repair and responses to genotoxic treatments, genomic instability and resistance to proteotoxic stress
Chromatin DNA damage response (DDR) is orchestrated by the E3 ubiquitin ligase ring finger protein 168 (RNF168), resulting in ubiquitin-dependent recruitment of DDR factors and tumor suppressors breast cancer ...
-
Article
IFNγ induces oxidative stress, DNA damage and tumor cell senescence via TGFβ/SMAD signaling-dependent induction of Nox4 and suppression of ANT2
Cellular senescence provides a biological barrier against tumor progression, often associated with oncogene-induced replication and/or oxidative stress, cytokine production and DNA damage response (DDR), leadi...
-
Article
Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact
Glioblastoma (GBM) is associated with poor prognosis despite aggressive surgical resection, chemotherapy, and radiation therapy. Unfortunately, this standard therapy does not target glioma cancer stem cells (G...
-
Article
Open AccessSETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair
Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-d...
-
Article
What a ‘Ku’incidence!: parallel discoveries of a new DNA repair factor
-
Article
Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells
Fractionated ionizing radiation combined with surgery or hormone therapy represents the first-choice treatment for medium to high-risk localized prostate carcinoma. One of the main reasons for the failure of r...
-
Article
Open AccessImmortalised breast epithelia survive prolonged DNA replication stress and return to cycle from a senescent-like state
Mammalian cells have mechanisms to counteract the effects of metabolic and exogenous stresses, many of that would be mutagenic if ignored. Damage arising during DNA replication is a major source of mutagenesis...
-
Article
Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells
Glioblastoma-initiating cells (GICs) are self-renewing tumorigenic sub-populations, contributing to therapeutic resistance via decreased sensitivity to ionizing radiation (IR). GIC survival following IR is att...
-
Article
The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis
Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor...
-
Article
A high resolution genomic portrait of bladder cancer: correlation between genomic aberrations and the DNA damage response
One major challenge in cancer research is to understand the complex interplay between the DNA damage response (DDR), genomic integrity, and tumor development. To address these issues, we analyzed 43 bladder tu...
-
Article
Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1
53BP1 is a mediator of DNA damage response (DDR) and a tumor suppressor whose accumulation on damaged chromatin promotes DNA repair and enhances DDR signaling. Using foci formation of 53BP1 as a readout in two...
-
Article
Multicentric breast cancer: clonality and prognostic studies
Clonality of multicentric breast cancer has traditionally been difficult to assess. We aimed to assess this using analysis of TP53 status (expression and mutation status). These results were then incorporated ...
-
Article
Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia
Maintaining genomic integrity is critical to avoid life-threatening disorders, such as premature aging, neurodegeneration and cancer. A multiprotein cascade operates at sites of DNA double-strand breaks (DSBs)...
-
Article
Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas
Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis an...
-
Article
Cytokine expression and signaling in drug-induced cellular senescence
Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal...
-
Article
The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer
The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast c...
-
Article
DNA damage signalling guards against activated oncogenes and tumour progression
DNA damage response (DDR), the guardian of genomic integrity, emerges as an oncogene-inducible biological barrier against progression of cancer beyond its early stages. Recent evidence from both cell culture a...
-
Article
DNA damage response mediators MDC1 and 53BP1: constitutive activation and aberrant loss in breast and lung cancer, but not in testicular germ cell tumours
MDC1 and 53BP1 are critical components of the DNA damage response (DDR) machinery that protects genome integrity and guards against cancer, yet the tissue expression patterns and involvement of these two DDR a...
